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J Orthop Res. 2019 Feb;37(2):386-396. doi: 10.1002/jor.24191. Epub 2018 Dec 17.

Two compartment pharmacokinetic model describes the intra-articular delivery and retention of rhprg4 following ACL transection in the Yucatan mini pig.

Author information

1
Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
2
Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts.
3
Department of Chemical Engineering, McMaster University, Hamilton, Ontario, Canada.
4
School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut.
5
Biomedical Engineering Department, University of Connecticut Health Center, Farmington, Connecticut.
6
Department of Emergency Medicine, Warren Alpert Medical School, Brown University, 1 Hoppin Street, Coro West Suite 112, Providence, Rhode Island, 02903.
7
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California.
8
Division of Biomedical Engineering, School of Engineering at Brown University, Providence, Rhode Island.

Abstract

Treatment of the injured joint with rhPRG4 is based on recent observations that inflammation diminishes expression of native PRG4. Re-establishing lubrication between pressurized and sliding cartilage surfaces during locomotion promotes the nascent expression of PRG4 and thus intra-articular (IA) treatment strategies should be supported by pharmacokinetic evidence establishing the residence time of rhPRG4. A total of 21 Yucatan minipigs weighing ∼55 kg each received 4 mg of 131 I-rhPRG4 delivered by IA injection 5 days following surgical ACL transection. Animals were sequentially euthanized following IA rhPRG4 at 10 min (time zero), 24, 72 h, 6, 13 and 20 days later. The decay of the 131 I-rhPRG4 was measured relative to a non-injected aliquot and normalized to the weight of cartilage samples, menisci and synovium, and known cartilage volumes from each compartment surface obtained from representative Yucatan minipig knees. Decay of 131 I-rhPRG4 from joint tissues best fit a two-compartment model with an α half-life (t1/2α ) of 11.28 h and β half-life (t1/2β ) of 4.81 days. The tibial and femoral cartilage, meniscii, and synovium retained 7.7% of dose at 24 h. High concentrations of rhPRG4 were found in synovial fluid (SF) that was non-aspiratable and resided on the articular surfaces, removable by irrigation, at 10 min following 131 I-rhPRG4 injection. Synovial fluid K21 exceeded K12 and SF t1/2β was 28 days indicating SF is the reservoir for rhPRG4 following IA injection. Clinical Significance: rhPRG4 following IA delivery in a traumatized joint populates articular surfaces for a considerable period and may promote the native expression of PRG4. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:386-396, 2019.

KEYWORDS:

PRG4; cartilage; half-life; lubricin; pharmacokinetics

PMID:
30488470
DOI:
10.1002/jor.24191
[Indexed for MEDLINE]

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